Project Summary Many disorders of mental health, including autism spectrum disorder (ASD) exhibit strong or, in some cases, exclusive, contributions from individual genomic variation. These types of genomic contribution are difficult, if not impossible, to accurately recapitulate in animal in vivo or cellular models. Human pluripotent stem cells (hPSCs) provide the opportunity to use state-of-the-art genetic tools to recreate individual genomic patterns of variation that contribute to, or cause, these disorders. In Project 1, we will develop optimized genome editing methods based on strategies previously developed in non-human models. We will engineer four fluorescent reporter and Cre driver lines (CTIP2-mCherry, GFAP-mCherry, CALB-mCherry-T2A-Cre, and GAD1-mCherry- T2A-Cre), a panel of four monogenic autism models: point mutations in MECP2, SHANK3, TSC2, and FMR1, and a panel of eight CNV autism models: reciprocal duplications and deletions at 7q11.23, 16p11.2, 17p11.2, and 15q11-13. We will also develop new strategies for haplotype exchange of hIPSC models.